THIS invention relates to the treatment and control of tuberculosis caused by Mycobacterium tuberculosis and in particular to the use of naphthoquinone derivatives in such treatment and control.
Tuberculosis (TB) remains a serious health problem in many regions of the world, especially in developing nations. It is a contagious disease and is becoming epidemic in some parts of the world. It is estimated that 30-60% of adults in developing countries are infected with Mycobacterium tuberculosis. Approximately 8-10 million individuals develop clinical TB and 3 million die of TB each year (WHO/IUATLD, 1989).
In South Africa, over 3 in every thousand people die of TB, the highest rate in the world, while one out of every 200 people suffers from active tuberculosis. Tuberculosis is the most commonly notified disease in South Africa and the fifth largest cause of death among the black population (South African Tuberculosis Association, 1998).
In the United States, the number of TB cases steadily decreased until 1986 when an increase was noted. Since then TB cases have continued to rise. Ten million individuals are infected in the U.S.A., with approximately 26000 new cases of active disease each year (National Jewish Medical and Research Center, 1994).
Individuals infected with Human Immunodeficiency Virus (HIV) are very susceptible to tuberculosis and often develop this disease before other manifestations of AIDS become apparent (Grange and Davey, 1990). Control of the TB epidemic linked with HIV infection will depend largely on the adequate treatment of TB, and possibly of effective chemoprophylaxis, not just for HIV-infected persons but for communities as well (WHO/IUATLD, 1989).
TB therapy has been revolutionized and the present treatment regimes for TB are based on multidrug therapy with usually 3 or 4 antituberculosis drugs. However, the problem of multidrug resistant tubercle bacilli is emerging for various drugs such as isoniazid, ethambutol, rifampicin and streptomycin, for example (Girling, 1989; Grange and Davey, 1990). Drug-resistant TB is very difficult to treat requiring greater numbers and varieties of medications for a longer period of treatment. The need for new antituberculosis agents is urgent due to the increasing resistance of mycobacteria to these classic antituberculosis drugs. A recent WHO report states that, globally, 2% of all cases of tuberculosis are multidrug resistantxe2x80x94by definition, resistance to rifampicin plus isoniazid (plus/minus other resistances). Such cases can be treated in the USA and other high resource regions but at a great cost ( greater than US$ 250,000 per case!) and using very long courses of rather toxic drugs, thereby raising serious problems of compliance (WHO, 1997). South Africa is witnessing an explosion in the number of cases of drug-resistant tuberculosis. In some parts of South Africa, 1 in 10 cases of TB is resistant to treatment (New Scientist, March 1997). It is essential to have new antituberculosis agents, preferably those that can readily and simply be produced from some local source.
According to a first aspect of the invention there is provided a naphthoquinone derivative of Formula 1: 
wherein,
R represents an OH group, methyl ether, ethyl ether or a similar ether;
R1 represents a methyl, ethyl or similar aliphatic hydrocarbon derivative;
R2 and R3 each independently represent hydrogen or a group selected from: 
wherein R5 represents an OH group, methyl ether, ethyl ether or a similar ether and R6 represents a methyl, ethyl or similar aliphatic hydrocarbon derivative;
R4 represents hydrogen or a group selected from: 
wherein R7 represents an OH group, methyl ether, ethyl ether or a similar ether and R8 represents a methyl, ethyl or similar aliphatic hydrocarbon derivative:
or pharmaceutically acceptable salts thereof, for use in a method of treating and/or controlling tuberculosis in a patient caused by Mycobacterium tuberculosis. 
According to a second aspect of the invention there is provided the use of a naphthoquinone derivative having the Formula 1 as set out above in the manufacture of a medicament for use in a method of treating and/or controlling tuberculosis in a patient caused by Mycobacterium tuberculosis. 
According to a third aspect of the invention there is provided a method of treating and/or controlling tuberculosis caused by Mycobacterium tuberculosis comprising administering to a patient in need thereof an effective amount of a naphthoquinone derivative having the Formula 1 as set out above.
The naphthoquinone derivative of Formula 1 is typically a compound of Formula 1a or Formula 1b: 
wherein R and R1 are as defined for Formula 1 above.
R in the compound of Formula 1a or 1b is preferably an OH group.
R1 in the compound of Formula 1a or 1b is preferably a CH3 group.
In particular, the naphthoquinone derivative of Formula 1 is 5,5xe2x80x2 dihydroxy 7,7xe2x80x2 binaphthoquinone (diospyrin) or 5-hydroxy-7-methyl-1,4-naphtoquinone (methyljuglone).